NDM has zinc at its active center, is one of metallo-β-lactamases having a broad substrate specificity, and, as with existing metallo-β-lactamases, decomposes β-lactam antibiotics other than monobactam (β-lactam agents.
NDM-1 has been detected for the first time from carbapenem-resistant Escherichia coli isolated from a patient transferred from New Delhi in India to Sweden in 2008. At the present time, there are reports about the detection of NDM-1, for example, from bacteria belonging to Enterobacteriaceae such as Klebsiella pneumoniae and Gram-negative bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii (non-patent document 1). NDM-1 is mainly present on plasmid DNA, and bacteria that have acquired the plasmid are rendered resistant to β-lactam antibiotics. In many cases, the plasmid holds a plurality of drug-resistant genes such as 16S rRNA methylase genes that impart a high level of resistance to aminoglycoside antibiotics and serine-β-lactamases that are monobactam β-lactam degradative enzymes (non-patent document 2).
Accordingly, NDM-1-producing bacteria are in many cases multidrug-resistant, and, thus, difficulties are encountered in the treatment with existing antibacterial agents. Enterobacteriaceae such as Escherichia coli are microorganisms causative of diseases that occur even in healthy individuals, such as uncomplicated cystitis. Thus, when NDM-1-producing bacteria spread, there is a possibility that the treatment with antimicrobial agents per se becomes difficult. Existing β-lactamase inhibitors such as clavulanic acid and tazobactam cannot inhibit metallo-β-lactamase such as NDM-1, and, thus, in β-lactam antibiotics that are now on the market, difficulties are encountered in the treatment of infectious diseases induced by NDM-1-producing bacteria (non-patent document 3).
Accordingly, NDM-1 inhibitors have been eagerly desired from the viewpoint of restoring the effectiveness of β-lactam antibiotics such as imipenem against NDM-1-producing bacteria.
Further, the present inventors have found in 2006 metallo-β-lactamase inhibitors that include maleic acid derivatives as active ingredients (patent document 1). In those days, however, there was no report about the isolation of NDM-1, and patent document 1 neither suggests nor discloses the inhibition of NDM-1.